The DOI matches its Crossref record; 27 of the 27 references it cites were found in a registry or an index.
Safety and clinical activity of pembrolizumab for treatment of recurrent or metastatic squamous cell carcinoma of the head and neck (KEYNOTE-012): an open-label, multicentre, phase 1b trial
Abstract
Background Patients with recurrent or metastatic squamous cell carcinoma of the head and neck have few treatment options. We aimed to assess the safety, tolerability, and antitumour activity of pembrolizumab, a humanised anti-programmed death receptor 1 (PD-1) antibody, in patients with PD-L1-positive recurrent or metastatic squamous cell carcinoma of the head and neck. Methods This study was an open-label, multicentre, phase 1b trial of patients with recurrent or metastatic squamous cell carcinoma of the head and neck. Patients were eligible for enrolment if they were aged 18 years or older, had a confirmed diagnosis of recurrent or metastatic squamous cell carcinoma of the head and neck, and had any level of PD-L1 expression (ie, at least 1% of tumour cells or stroma that were PD-L1-positive by immunohistochemistry). Patients received pembrolizumab 10 mg/kg intravenously every 2 weeks. Primary outcomes were safety in the per-protocol population and the proportion of patients with centrally reviewed overall response per Response Evaluation Criteria In Solid Tumors (RECIST, version 1.1). Overall response was analysed in the full analysis set, which was defined as all patients who had received at least one dose of pembrolizumab, had measurable disease at baseline, and one post-baseline scan or patients without a post-baseline scan who discontinued therapy because of disease progression or a drug-related adverse event. The study is registered with ClinicalTrials.gov, number NCT…
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“These findings highlight virus-specific T cells in anti-tumor responses during ICB.”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [78]
In the citing paper
“Clinical studies show enhanced responses to PD-1 blockade in HNSCC patients with human papillomavirus infection compared to those without.78”
From Contrasting cytotoxic and regulatory T cell responses underlying distinct clinical outcomes to anti-PD-1 plus lenvatinib therapy in cancer (2025) · cites this paper as [78]
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“PD-1 antibodies have been approved for treatment of head and neck squamous cell carcinoma [11, 12] but the role of PD-L1 expression and immunotherapy in non-squamous head and neck tumors, including salivary gland malignancies, has not been completely elucidated.”
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“PDL1 overexpression has been noted on multiple solid tumor types, with about 60% of human papillomavirus (HPV)–positive HNSCC tumors expressing this ligand (Concha-Benavente et al. 2016).”
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“The phase Ib KEYNOTE 012 trial (n = 60) and phase II KEYNOTE 055 trial (n = 171) treated R/M SCCHN patients with the ICI pembrolizumab and noted a 22% and 32% ORR in HPV+ SCCHN compared to 16% and 14% in HPV− SCCHN, respectively [58,59].”
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“In HNSCC, anti-PD-1 antibodies nivolumab and pembrolizumab have been both approved by the USA Food and Drug Administration (FDA) and European Medicine’s Agency (EMA) for platinum-refractory R/M disease based on landmark clinical trials demonstrating superior OS or durable response rate (RR), respectively, in patients…”
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Challenges in Combining Immunotherapy with Radiotherapy in Recurrent/Metastatic Head and Neck Cancer
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“Even though pseudoprogression was observed in only 2–4% of HNSCC cases treated with ICI, this possibility should be kept in mind when progression to ICI is suspected [169,170].”
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“[15], non-small cell lung cancer [12], renal cell cancer [13], urothelial cancer [11], and relapsed or refractory Hodgkin’s lymphoma [14].”
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Liver toxicity in the era of immune checkpoint inhibitors: A practical approach
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“In this study, analysis of PD-L1 showed an increase in ORR between PD-L1 positive versus PD-L1 negative tumors (P = 0.23) when both tumor and stromal cells were used to score PD-L1 [65].”
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Multidisciplinary Care of the Head and Neck Cancer Patient
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“In recent years, various biomarkers have been developed to assist in the selection of anticancer agents [6,7], including PD-L1 expression [8,9], tumor mutation burden [10], interferonγ signature [11], and the tumor microenvironment [12].”
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BackgroundDe-Escalating Strategies in HPV-Associated Head and Neck Squamous Cell Carcinoma
Economopoulou, P., Kotsantis, I., & Psyrri, A. (2021) · Viruses · doi:10.3390/v13091787 · Cited by 21
“A very tempting approach is the incorporation of immunotherapy in de-escalation strategies, since HPV+ OPSCC has an immunogenic profile and has been found to produce high response rates with immunotherapy [47].”
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“In the last 20 years, only two new targeted therapeutics have been approved for clinical use [13]: cetuximab-based immunotherapy in 2006 [14] and nivolumab- and pembrolizumab-based immunotherapy in 2016 [15] and 2017 [16], respectively.”
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“In head and neck cancer (HNC), the correlation between hypoxia and the efficacy of immune checkpoint inhibitors has been confirmed, and subsets of HNC have been identified based on the characteristics of hypoxia immunity (10-12).”
BackgroundThe roles of programmed death ligand 1 in virus-associated cancers
Mofrad, M. G., Maleki, D. T., & Faghihloo, E. (2020) · Infection Genetics and Evolution · doi:10.1016/j.meegid.2020.104368 · Cited by 23
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“The phase II KEYNOTE 012 clinical trial of the pembroluzimab programmed cell death protein 1 (PD‐1) blockade had an 18% overall response rate in recurring and metastatic HNSCC.(18,19)”
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“These treatments have become increasingly and widely used with efficacy demonstrated in multiple tumor types including melanoma (1–3), non-small cell lung cancer (NSCLC) (4–10), head and neck squamous cell carcinoma (11, 12) and renal cell carcinoma (RCC) (13).”
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Advances in T-cell checkpoint immunotherapy for head and neck squamous cell carcinoma
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“Further updates on this trial reported that pembrolizumab was twice as effective as cetuximab in HNSCC, with disease control of 50% and tumor shrinkage in 57% of patients.(77) In a combined update of two cohorts of patients with R/M HNSCC that was heavily pre-managed,”
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AACR Cancer Progress Report 2016
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“However, initial results show that nivolumab and pembrolizumab may benefit some patients with head and neck cancer (162, 163), and that pembrolizumab may benefit a subgroup of patients with colorectal cancer (164).”
Choi, S.-W., Kim, J. H., Hong, J., & Kwon, M. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1568590 · Cited by 22
Immune checkpoint inhibitors in gastrointestinal malignancies: an Umbrella review
Noori, M., Jafari‐Raddani, F., Davoodi‐Moghaddam, Z., Delshad, M., Safiri, S., & Bashash, D. (2024) · Cancer Cell International · doi:10.1186/s12935-023-03183-3 · Cited by 26
“…anti-programmed-death ligand 1 (PD-L1), and anti-CTLA-4 medications like Nivolumab, Pembroli-zumab, and Atezolizumab achieved FDA approval for non-small-cell lung cancer (NSCLC) [9–11], renal cell carcinoma [12, 13], head and neck squamous cell carcinoma [14, 15], and urothelial cancer [16].”
BackgroundKang, D., Liu, S.-P., Yuan, X., Liu, S.-X., Zhang, Z.-R., He, Z.-M., Yin, X.-D., & Mao, H.-Y. (2023) · Journal of Cancer Research and Clinical Oncology · doi:10.1007/s00432-023-05504-5 · Cited by 20
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“However, they suffer from high costs, side effects, and insignificant results in patients not receiving platinum-based therapy (Seiwert et al. 2016; Ferris et al. 2016; Ferris et al. 2018).”
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“Pembrolizumab also proved to be effective in HPV-positive patients, with 25% of patients showing an impressive response [63].”
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Immune Checkpoint Inhibitor-induced Pneumonitis: Incidence, Clinical Characteristics, and Outcomes
Banavasi, H. V. R., Kim, S., Alkassis, S., Daoud, A., Laktineh, A., Nagasaka, M., Sukari, A. W., & Soubani, A. O. (2021) · Hematology/Oncology and Stem Cell Therapy · doi:10.1016/j.hemonc.2021.09.005 · Cited by 21
Clarke, E., Eriksen, J. G., & Barrett, S. (2021) · Acta Oncologica · doi:10.1080/0284186x.2021.1964699 · Cited by 25
“[14] enrolled PD-L1 positive patients only.”
BackgroundResultInfluentialZhao, Y., Liu, L., & Weng, L. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.714483 · Cited by 24
“Further phase 1b trials demonstrated that pembrolizumab exhibited antitumor activity in advanced triple-negative breast cancer (TNBC) (Nanda et al., 2016), advanced gastric cancer (GC) (Muro et al., 2016), HNSCC (Seiwert et al., 2016) and UC (Plimack et al., 2017).”
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Emerging role of immune checkpoint inhibitors and predictive biomarkers in head and neck cancers
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Drug resistance in cancer immunotherapy: new strategies to improve checkpoint inhibitor therapies
Rodríguez-Pascual, J., Ayuso‐Sacido, Á., & Belda-Iniesta, C. (2019) · Cancer Drug Resistance · doi:10.20517/cdr.2019.61 · Cited by 17
“As monotherapy, Pembrolizumab is indicated for the adjuvant treatment of stage III melanoma after complete resection and, in the metastatic setting, for advanced melanoma, non-small cell lung carcinoma (NSCLC), relapse or refractory cHL, platinum-resistant urothelial carcinoma and head and neck squamous cell carcinoma…”
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“These agents have demonstrated significant promise with response rates of 13%-18%.(7,8) Although these agents provide meaningful activity for patients with recurrent or metastatic disease, a majority of patients do not respond to immune modulating therapy and both constitutive and acquired resistance remain common pro…”
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“treatment of many patients with advanced cancer using antibodies against PD-L1 has been demonstrated, including HNSCC [43].”
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Head and neck cancer patient-derived tumouroid cultures: opportunities and challenges
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“Tumouroid culture model systems have been further developed using different methods, such as microcarriers [34], air-liquid interface (ALI) method [35, 36], Microfluidic device, Organoid-OnA-Chip models [28, 34], and organoids with bioreactors [34, 37].”
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“demonstrated encouraging improvements in survival outcomes in patients with EC.(4,5) Accumulating evidence has demonstrated the impact of the TME on immunotherapy.”
BackgroundChao, J. L., Korzinkin, M., Zhavoronkov, A. A., Ozerov, I. V., Walker, M. T., Higgins, K. E., Lingen, M. W., Izumchenko, E., & Savage, P. A. (2021) · Cell Reports Medicine · doi:10.1016/j.xcrm.2021.100399 · Cited by 24
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Immune Response Checkpoint Inhibitors: New Risks of a New Class of Antitumor Agents
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“Recently, the FDA (Food and Drug Administration) approved the immune checkpoint programmed cell death protein 1 (PD-1) inhibitor pembrolizumab for the treatment of HNSCC, regardless of human papillomavirus expression [5].”
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Immunotherapy for Head and Neck Cancer
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“Nearly 40% of pathologic specimens demonstrate the presence of tumor infiltrating lymphocytes, providing a rationale for the efficacy of CPI [74].”
BackgroundInfluential
Metadata
- Authors
- Seiwert, T. Y., Burtness, B., Mehra, R., Weiss, J., Berger, R., Eder, J. P., Heath, K., McClanahan, T., Lunceford, J., Gause, C., Cheng, J. D., & Chow, L. Q.
- Affiliations
- University of Chicago (US)
- Fox Chase Cancer Center (US)
- University of North Carolina at Chapel Hill (US)
- Sheba Medical Center (IL)
- Yale Cancer Center (US)
- Merck & Co., Inc., Rahway, NJ, USA (United States) (US)
- University of Washington (US)
- Corresponding author
- Seiwert, Tanguy Y
- ORCID
- Venue
- The Lancet Oncology
- Publisher
- Elsevier BV
- Published
- 2016-07
- Volume
- 17
- Issue
- 7
- Pages
- 956-965
- ISSN
- 1470-2045 (ISSN-L)
- OpenAlex
- W2401455386
- Cited by
- 1,745
- References
- 0
- Citations by year
- 2026: 73 · 2025: 136 · 2024: 149 · 2023: 159 · 2022: 165 · 2021: 213 · 2020: 195 · 2019: 190 · 2018: 216 · 2017: 204 · 2016: 44
- FWCI
- 117.58
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Lancet Oncology (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Oncology › Cancer Immunotherapy and Biomarkers
- Health Sciences › Medicine › Otorhinolaryngology › Head and Neck Cancer Studies
- Health Sciences › Medicine › Dermatology › Nonmelanoma Skin Cancer Studies
- Keywords
- pembrolizumab, PD-1 inhibitors, PD-L1 expression, immune checkpoint inhibitors, antitumour activity, drug safety and tolerability, immune-related adverse events, hyponatremia, elevated liver enzymes, overall response rate
- MeSH terms
- Adult, Aged, Aged, 80 and over, Antineoplastic Agents, Carcinoma, Squamous Cell, Female, Follow-Up Studies, Head and Neck Neoplasms, Humans, Lymphatic Metastasis, Male, Middle Aged, Neoplasm Recurrence, Local, Neoplasm Staging, Prognosis, Safety, Survival Rate, Young Adult, Antibodies, Monoclonal, Humanized
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